HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder
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Research Article Oncology Pulmonology

HNF4α controls growth, identity, and KRAS inhibitor response in invasive mucinous adenocarcinoma of the lung

Abstract

Cellular plasticity is a hallmark of cancer, enabling tumor cells to alter identity and evade therapeutic pressure. In invasive mucinous adenocarcinoma of the lung (IMA), NK2 homeobox 1 (NKX2-1) loss triggers a pulmonary to gastric switch marked by aberrant activation of hepatocyte nuclear factor 4 alpha (HNF4α), a master regulator of gastrointestinal/hepatic differentiation. We show that HNF4α promoted IMA growth and activated a gastric pit cell–like program. Loss of HNF4α enabled forkhead box A1 and A2 (FoxA1/2) transcription factors to bind de novo sites and activate alternative, nongastric identities in IMA. HNF4α also established a mucinous program associated with tolerance to KRAS blockade, and loss of HNF4α enhanced response to KRASG12D inhibition. Mechanistically, HNF4α blocked cell-cycle exit in drug-tolerant persister cells and promoted activity of the antioxidant transcription factor nuclear factor erythroid 2–related factor 2 (NRF2). NRF2 activation partially rescued the effects of Hnf4a deletion on KRASG12D inhibition, whereas NRF2 inhibition enhanced sensitivity to KRASG12D blockade. Thus, HNF4α is a key regulator of growth, identity, and primary response to KRASG12D inhibition in IMA.

Authors

Headtlove Essel Dadzie, Yangsook Song Green, Soledad A. Camolotto, Henry U. Arnold, Matthew Gumbleton, Minzhe Guo, Mari Mino-Kenudson, Yutaka Maeda, Benjamin T. Spike, Eric L. Snyder

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Figure 4

HNF4α constraints cellular heterogeneity in IMA at single-cell resolution.

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HNF4α constraints cellular heterogeneity in IMA at single-cell resolutio...
(A) Uniform manifold approximation and projection (UMAP) of malignant KN (5,001 cells) and KNH (5,024 cells) GEMM tumors (n = 2 mice per genotype, multiple tumors per mouse) colored by Seurat clusters. (B) UMAP of KN and KNH tumor cells colored by genotype. (C) Total tumor cells in groups A and B. (D) Proportion of KN and KNH tumor cells in groups A and B. (E) Distribution of tumor cells from each genotype across Seurat clusters. (F) GSEA of C8 cell-type signatures using DEGs comparing groups A and B. (G) UMAPs of tuft cell marker genes (Pou2f3, Ptprc, Dclk1, and Lrmp). (H) Representative IHC images of DCLK1 and POU2F3 staining in KN and KNH GEMM tumors at 14 weeks PTI. Scale bar: 50 μm. Arrows indicate POU2F3-positive tumor cells. (I) UMAP showing enrichment of neuron-like (cluster 1) and immune-like (cluster 2) tuft-like cells in KN and KNH tumors in group A (PMID: 29144463).